[unreadable] Sepsis remains a leading cause of mortality in the United States, and it and other causes of poorly controlled systemic inflammation, such as trauma, hemorrhagic shock and acute pancreatitis, often lead to dysfunction of multiple organs (i.e., the so-called "multiple organ dysfunction syndrome" or MODS). The pathological mechanisms underlying the development of MODS are poorly understood. This proposal is designed to provide me with the resources and training necessary to achieve two goals. First it will allow me to become a successful and independent scientific investigator in critical care medicine. Secondly, it will allow me to advance of my understanding of the mechanisms underlying HMGB 1-mediated organ dysfunction in critical illness and serve as a scaffold for providing me with additional training in critical research methods, including statistical analyses of data, Western blotting, and immunohistochemistry. As my career progresses, I would like to develop skills that will enable me to better understand the relationship between sepsis/inflammation and the multiple organ dysfunction syndrome. Through these activities, I will develop more sophisticated approaches for attacking problems "at the bench," new approaches for experimental design, a better understanding of how to best carry out data analysis including the use of advanced statistical methods. I have provided a detailed plan for my didactic training with formal course work. In relation to my research goals, I have systematically addressed my hypothesis under two interrelated Specific Aims. In specific aim 1 I will determine whether HMGB 1 causes (NO.)-dependent derangements in the expression of important tight junction proteins using the Caco-2 human enterocyte-like cell line. In specific aim 2 we will determine whether HMGB1 alters the expression of tight junction proteins in mouse gut epithelium, liver, lung, and kidney. This proposal will lead to improved understanding in HMGB 1-mediated organ dysfunction in critical illness. Success of this proposal may lay the groundwork for future advancements in caring for the critically ill patient. [unreadable] [unreadable]